Proteasomal Protein Degradation: Adaptation of Cellular Proteolysis With Impact on Virus—and Cytokine-Mediated Damage of Heart Tissue During Myocarditis

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  Figure 1. Impact of i-proteasome subunits on innate immune signaling in myeloid cells. Among many different pattern recognition receptors, TLRs are sensors of microbial antigens on monocytes/macrophages and dendritic cells. These membrane-bound receptors are located both on the cellular surface (TLR4—colored in red) and in endosomes (TLR3—green, TLR7—blue, TLR9—purple) (101). Signaling pathways down-stream of TLR4, TLR7, and TLR9 involve the common adaptor molecule MyD88 (130, 131). Upon TLR stimulation, the ubiquitin E3 ligase TRAF6 engages with the TLR/MyD88 complex and generates poly-ubiquitin scaffolds (132), thereby recruiting the TAK1 complex (133). TAK1 then activates the IKK complex, which in turn phosphorylates IκBα. Ubiquitination of IκBα marks it for degradation by the proteasome. Thereafter, NF-κB translocates into the nucleus. Simultaneously, TAK1 induces MAP kinase signaling (134), which results in the phosphorylation of ERK1/2, p38, and JNK and thereby activates the transcription factor AP-1. Both NF-κB and AP-1 induce the expression of co-stimulatory molecules (CD80, CD86, CD40) and migration signals (CCR7) on DCs, the secretion of pro-inflammatory cytokines (e.g., TNF-α,…

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  Figure 2. Regulation of NF-κB signaling by the proteasome. Multiple inflammatory signals result in the activation of the transcription factor NF-κB through a variety of adapter proteins and kinases. The most abundant form of the NF-κB dimer is the p50/p65 heterodimer. (A) The p105 precursor is processed by the proteasome, thereby liberating the NF-kB p50 subunit for dimerization with p65. IκB retains the NF-κB heterodimer in the cytoplasm. (B) Ligand binding to cellular receptors like TLRs activates the IKK complex, which catalyzes the phosphorylation of IκB, inducing its poly-ubiquitination and degradation by the proteasome. (C) Activated NF-κB translocates into the nucleus, where it (D) activates target gene expression. Table 2 summarizes all reported effects of i-proteasome activity on the different steps in this canonical NF-κB signaling pathway. NF-kB, nuclear factor kappa B; IκBs, inhibitors of κB; IKK, IκB kinase.